Muscle protein wasting occurs in human immunodeficiency virus (HIV)-infected individuals and is often the initial indication of acquired immunodeficiency syndrome (AIDS). The alterations in muscle protein metabolism that occur with HIV-infection are unknown. Seven subjects with AIDS-wasting (CD4<200/mm3), chronic stable opportunistic infections (OI) and >10% weight loss, 10 HIV-infected men and 1 woman (CD4>200/mm3) without wasting or OI (asymptomatic), and 6 HIV-negative lean men (control) received a constant intravenous infusion of 1-[13C]-leucine and 2-[15N]-glutamine. Plasma leucine and glutamine rate of appearance (Ra), whole-body leucine turnover, disposal and oxidation rates, and 13C-leucine incorporation rate into mixed muscle protein were assessed. Fasting whole-body proteolysis and synthesis rates were increased (P<0.05) above control (129 and 96 (mol/kg FFM/h) in the asymptomatic HIV-infected subjects (145 and 110 (mol/kg FFM/h), and further increased (P< 0.05) in A IDS-wasting subjects (153 and 123 (mol/kg FFM/h). Fasting mixed muscle protein synthesis rate was increased in the asymptomatic subjects (0.062 %/h; P<0.05), but similar in AIDS-wasting and control subjects (0.036 vs 0.037 %/h). Plasma glutamine Ra was increased (P<0.001) in AIDS-wasting subjects (528 (mol/kg FFM/h), but similar in control and asymptomatic subjects (408 and 390 (mol/kg FFM/h). These findings suggest that AIDS-wasting results from; (a) a preferential reduction in muscle protein, (b) a failure to sustain an elevated rate of mixed muscle protein synthesis while whole-body protein turnover is increased, and (c) a significant increase in glutamine release into the circulation, probably from muscle. Several interesting possibilities exist for the increased glutamine Ra in AIDS-wasting.